Discrimination between healthy participants and people with panic disorder based on polygenic scores for psychiatric disorders and for intermediate phenotypes using machine learning.

OBJECTIVE: Panic disorder is a modestly heritable condition. Currently, diagnosis is based only on clinical symptoms; identifying objective biomarkers and a more reliable diagnostic procedure is desirable. We investigated whether people with panic disorder can be reliably diagnosed utilizing combinations of multiple polygenic scores for psychiatric disorders and their intermediate phenotypes, compared with single polygenic score approaches, by applying specific machine learning techniques. METHODS: Polygenic scores for 48 psychiatric disorders and intermediate phenotypes based on large-scale genome-wide association studies (n = 7556-1,131,881) were calculated for people with panic disorder (n = 718) and healthy controls (n = 1717). Discrimination between people with panic disorder and healthy controls was based on the 48 polygenic scores using five methods for classification: logistic regression, neural networks, quadratic discriminant analysis, random forests and a support vector machine. Differences in discrimination accuracy (area under the curve) due to an increased number of polygenic score combinations and differences in the accuracy across five classifiers were investigated. RESULTS: All five classifiers performed relatively well for distinguishing people with panic disorder from healthy controls by increasing the number of polygenic scores. Of the 48 polygenic scores, the polygenic score for anxiety UK Biobank was the most useful for discrimination by the classifiers. In combinations of two or three polygenic scores, the polygenic score for anxiety UK Biobank was included as one of polygenic scores in all classifiers. When all 48 polygenic scores were used in combination, the greatest areas under the curve significantly differed among the five classifiers. Support vector machine and logistic regression had higher accuracy than quadratic discriminant analysis and random forests. For each classifier, the greatest area under the curve was 0.600 ± 0.030 for logistic regression (polygenic score combinations N = 14), 0.591 ± 0.039 for neural networks (N = 9), 0.603 ± 0.033 for quadratic discriminant analysis (N = 10), 0.572 ± 0.039 for random forests (N = 25) and 0.617 ± 0.041 for support vector machine (N = 11). The greatest areas under the curve at the best polygenic score combination significantly differed among the five classifiers. Random forests had the lowest accuracy among classifiers. Support vector machine had higher accuracy than neural networks. CONCLUSIONS: These findings suggest that increasing the number of polygenic score combinations up to approximately 10 effectively improved the discrimination accuracy and that support vector machine exhibited greater accuracy among classifiers. However, the discrimination accuracy for panic disorder, when based solely on polygenic score combinations, was found to be modest.

Effect of an Internet-Delivered Cognitive Behavioral Therapy-Based Sleep Improvement App for Shift Workers at High Risk of Sleep Disorder: Single-Arm, Nonrandomized Trial.

BACKGROUND: Shift workers are at high risk of developing sleep disorders such as shift worker sleep disorder or chronic insomnia. Cognitive behavioral therapy (CBT) is the first-line treatment for insomnia, and emerging evidence shows that internet-based CBT is highly effective with additional features such as continuous tracking and personalization. However, there are limited studies on internet-based CBT for shift workers with sleep disorders. OBJECTIVE: This study aimed to evaluate the impact of a 4-week, physician-assisted, internet-delivered CBT program incorporating machine learning-based well-being prediction on the sleep duration of shift workers at high risk of sleep disorders. We evaluated these outcomes using an internet-delivered CBT app and fitness trackers in the intensive care unit. METHODS: A convenience sample of 61 shift workers (mean age 32.9, SD 8.3 years) from the intensive care unit or emergency department participated in the study. Eligible participants were on a 3-shift schedule and had a Pittsburgh Sleep Quality Index score ≥5. The study comprised a 1-week baseline period, followed by a 4-week intervention period. Before the study, the participants completed questionnaires regarding the subjective evaluation of sleep, burnout syndrome, and mental health. Participants were asked to wear a commercial fitness tracker to track their daily activities, heart rate, and sleep for 5 weeks. The internet-delivered CBT program included well-being prediction, activity and sleep chart, and sleep advice. A job-based multitask and multilabel convolutional neural network-based model was used for well-being prediction. Participant-specific sleep advice was provided by sleep physicians based on daily surveys and fitness tracker data. The primary end point of this study was sleep duration. For continuous measurements (sleep duration, steps, etc), the mean baseline and week-4 intervention data were compared. The 2-tailed paired t test or Wilcoxon signed rank test was performed depending on the distribution of the data. RESULTS: In the fourth week of intervention, the mean daily sleep duration for 7 days (6.06, SD 1.30 hours) showed a statistically significant increase compared with the baseline (5.54, SD 1.36 hours; P=.02). Subjective sleep quality, as measured by the Pittsburgh Sleep Quality Index, also showed statistically significant improvement from baseline (9.10) to after the intervention (7.84; P=.001). However, no significant improvement was found in the subjective well-being scores (all P>.05). Feature importance analysis for all 45 variables in the prediction model showed that sleep duration had the highest importance. CONCLUSIONS: The physician-assisted internet-delivered CBT program targeting shift workers with a high risk of sleep disorders showed a statistically significant increase in sleep duration as measured by wearable sensors along with subjective sleep quality. This study shows that sleep improvement programs using an app and wearable sensors are feasible and may play an important role in preventing shift work-related sleep disorders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/24799.

Association of Serotonin Transporter Gene (5-HTTLPR/rs25531) Polymorphism with Comorbidities of Panic Disorder.

INTRODUCTION: Panic disorder (PD) has many comorbidities such as depression, bipolar disorder (BPD), and agoraphobia (AG). PD is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Recently, a tri-allelic serotonin transporter (5-HTTLPR/rs25531) polymorphism was reported to be more sensitive to personality traits compared to the bi-allelic 5-HTTLPR polymorphism. We hypothesized that the 5-HTTLPR/rs25531 polymorphism may lead to a pathological anxious state depending on the presence or absence of a comorbidity in PD. METHODS: In this study, we investigated the relationship between comorbidities in PD and tri-allelic 5-HTTLPR polymorphisms. A total of 515 patients with PD (148 males, 367 females) were genotyped, and the Revised NEO Personality Inventory as well as anxiety-related psychological tests were administered. Depression, BPD, and AG were diagnosed as comorbidities. RESULTS: For the tri-allele 5-HTTLPR genotype, a significant interaction effect was found between openness to experience and comorbid depression. Examination of the interaction between AG and the tri-allelic 5-HTTLPR genotype revealed that L' allele carriers are associated with higher trait anxiety than the S'S' genotype group in PD without AG. CONCLUSION: Some anxiety and personality traits can be characterized by the tri-allelic gene effect of 5-HTTLPR. These results suggest that tri-allelic 5-HTTLPR genotypes have genetic effects on the presence of comorbidities of PD.

Shared genetic etiology between anxiety disorders and psychiatric and related intermediate phenotypes.

BACKGROUND: Psychiatric disorders and related intermediate phenotypes are highly heritable and have a complex, overlapping polygenic architecture. A large-scale genome-wide association study (GWAS) of anxiety disorders identified genetic variants that are significant on a genome-wide. The current study investigated the genetic etiological overlaps between anxiety disorders and frequently cooccurring psychiatric disorders and intermediate phenotypes. METHODS: Using case-control and factor score models, we investigated the genetic correlations of anxiety disorders with eight psychiatric disorders and intermediate phenotypes [the volumes of seven subcortical brain regions, childhood cognition, general cognitive ability and personality traits (subjective well-being, loneliness, neuroticism and extraversion)] from large-scale GWASs (n = 7556-298 420) by linkage disequilibrium score regression. RESULTS: Among psychiatric disorders, the risk of anxiety disorders was positively genetically correlated with the risks of major depressive disorder (MDD) (rg ± standard error = 0.83 ± 0.16, p = 1.97 × 10-7), schizophrenia (SCZ) (0.28 ± 0.09, p = 1.10 × 10-3) and attention-deficit/hyperactivity disorder (ADHD) (0.34 ± 0.13, p = 8.40 × 10-3). Among intermediate phenotypes, significant genetic correlations existed between the risk of anxiety disorders and neuroticism (0.81 ± 0.17, p = 1.30 × 10-6), subjective well-being (-0.73 ± 0.18, p = 4.89 × 10-5), general cognitive ability (-0.23 ± 0.08, p = 4.70 × 10-3) and putamen volume (-0.50 ± 0.18, p = 5.00 × 10-3). No other significant genetic correlations between anxiety disorders and psychiatric or intermediate phenotypes were observed (p > 0.05). The case-control model yielded stronger genetic effect sizes than the factor score model. CONCLUSIONS: Our findings suggest that common genetic variants underlying the risk of anxiety disorders contribute to elevated risks of MDD, SCZ, ADHD and neuroticism and reduced quality of life, putamen volume and cognitive performance. We suggest that the comorbidity of anxiety disorders is partly explained by common genetic variants.

Do postpartum anxiety and breastfeeding self-efficacy and bonding at early postpartum predict postpartum depression and the breastfeeding method?

We investigated whether postpartum anxiety (PPA) and breastfeeding self-efficacy and bonding at the early postpartum period can be used to predict postpartum depression and the breastfeeding method, and we sought to identify factors related to postpartum depression. Of the 510 eligible women, 185 (36%) returned the questionnaire on all three occasions (1 day, 3 days, and 1 month after childbirth). The mothers' progress on the State-Trait Anxiety Inventory (STAI), Breastfeeding Self-Efficacy Scale Short Form (BFSES-SF), and Postnatal Bonding Questionnaire (PBQ) was observed over three periods. A repeated-measures ANOVA revealed that the mothers at high risk of developing postpartum depression (PPD) were those who did not show an increase in BFSES-SF score at early postpartum, and mothers whose bonding disorders have deteriorated rapidly. The results of the logistic regression analysis revealed a significant difference in employment as a factor related to postpartum depression. Compared to Regular, Part-time status was 4.4 times more likely and Unemployed status was 2.3 times more likely to cause postpartum depression. For the early detection of PPD, it is necessary to identify (1) mothers who do not show an increase in the BFSES-SF score, (2) mothers whose bonding disorders have deteriorated rapidly, and (3) part-time or unemployed mothers as characteristic of postpartum depression.

Investigamos si la ansiedad posterior al parto (PPA) y la autoeficacia de amamantar y establecer afectividad en el período posterior al parto pueden usarse para predecir la depresión posterior al parto y el método de amamantar, así como también nos propusimos identificar factores relacionados con la depresión posterior al parto. De las 510 mujeres elegibles, 185 (36%) devolvieron el cuestionario en todas las tres ocasiones (1 día, 3 días y 1 mes después de haber dado a luz). A lo largo de tres períodos, se observó el progreso de las madres en el Inventario para Medir el Estado y Características de la Ansiedad (STAI), el Formulario Corto de la Escala de Autoeficacia de Amamantar (BFSES-SF) y el Cuestionario de Afectividad Postnatal (PBQ). Medidas repetidas ANOVA revelaron que las madres bajo alto riesgo de desarrollar depresión posterior al parto (PPD) eran aquellas que no mostraron un incremento en los puntajes BFSES-SF en el temprano período de postparto, y las madres cuyos trastornos de afectividad habían mejorado rápidamente. Los resultados de los análisis de regresión logística revelaron una diferencia significativa en el empleo como factor relacionado con la depresión posterior al parto. Comparado con el empleo regular, la condición de empleo de tiempo parcial fue 4.4 veces más probable y la condición de desempleo fue 2.3 veces más probable de ser causa de la depresión posterior al parto. Para la detección temprana de PPD, es necesario identificar (1) madres que no muestran un incremento en el puntaje BFSES-SF, (2) madres cuyos trastornos de afectividad han mejorado rápidamente, y (3) madres con empleos de tiempo parcial o desempleadas como característica de la depresión posterior al parto. Palabras claves: Autoeficacia de amamantar, afectividad, depresión posterior al parto, método de amamantar.

Nous nous sommes interrogés si l'anxiété postpartum (PPA) et l'auto-efficacité de l'allaitement au sein et du lien au début de la période postpartum peuvent être utilisées afin de prédire la dépression postpartum et la méthode d'allaitement au sein, et nous avons essayé d'identifier les facteurs liés à la dépression postpartum. Sur 510 femmes admissibles, 185 (36%) ont renvoyé le questionnaire aux trois occasions (1 jour, 3 jours, et 1 mois après la naissance). Le progrès des mères sur l'Inventaire de l'Etat et du Trait d'Anxiété (en anglais State-Trait Anxiety Inventory, soit STAI), le Formulaire Court de l'Echelle d'Auto-Efficacité de l'Allaitement (Breastfeeding Self-Efficacy Scale Short Form, soit BFSES-SF), et le Questionnaire de Lien Postnatale (Postnatal Bonding Questionnaire, soit PBQ) ont été observés au fil de trois périodes. Des mesures répétées ANOVA ont révélé que les mères à haut risque de développer une dépression postpartum (PPD) étaient celles qui n'avaient pas fait preuve d'une augmentation dans le score BFSES-SF dans la première période postpartum, et les mères dont les troubles du lien s'étaient améliorés rapidement. Les résultats de l'analyse de régression logistique ont révélé une différence importante dans l'emploi en tant que facteur lié à la dépression postpartum. Comparé à un statut d'Emploi Normal, le statut de Temps partiel était 4,4 fois plus à même de causer une dépression postpartum et le statut de Sans emploi était 2,3 fois plus à même de causer une dépression postpartum. Pour la détection précoce de la PPD il est nécessaire d'identifier (1) les mères qui ne font pas preuve d'une augmentation dans le score BFSES-SF, (2) les mères dont les troubles du lien se sont améliorés rapidement et (3) les mères travaillant à temps partiel ou sans emploi comme caractéristiques de la dépression postpartum. Mots clés: auto-efficacité de l'allaitement au sein, Lien, EPDS, dépression postpartum, méthode d'allaitement au sein.

An epigenome-wide methylation study of healthy individuals with or without depressive symptoms.

Major depressive disorder is a common psychiatric disorder that is thought to be triggered by both genetic and environmental factors. Depressive symptoms are an important public health problem and contribute to vulnerability to major depression. Although a substantial number of genetic and epigenetic studies have been performed to date, the detailed etiology of depression remains unclear and there are no validated biomarkers. DNA methylation is one of the major epigenetic modifications that play diverse roles in the etiology of complex diseases. In this study, we performed an epigenome-wide association study (EWAS) of DNA methylation on subjects with (N = 20) or without (N = 27) depressive symptoms in order to examine whether different levels of DNA methylation were associated with depressive tendencies. Employing methylation-array technology, a total of 363,887 methylation sites across the genomes were investigated and several candidate CpG sites associated with depressive symptoms were identified, especially annotated to genes linked to a G-protein coupled receptor protein signaling pathway. These data provide a strong impetus for validation studies using a larger cohort and support the possibility that G-protein coupled receptor protein signaling pathways are involved in the pathogenesis of depression.

Evaluation of polygenic risks for narcolepsy and essential hypersomnia.

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*06:02=2.30 × 10-48, Pwhole genome without HLA-DQB1*06:02=6.73 × 10-2) including HLA-DQB1*06:02 effects and 1.3% (Pwhole genome without HLA-DQB1*06:02=2.43 × 10-2) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*06:02=9.74 × 10-2). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, PHLA-DQB1*06:02=7.02 × 10-14, Pwhole genome without HLA-DQB1*06:02=1.34 × 10-1, EHS without HLA-DQB1*06:02: 0.4%, Pwhole genome without HLA-DQB1*06:02=3.06 × 10-1). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.

Immune-related pathways including HLA-DRB1(∗)13:02 are associated with panic disorder.

Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Both genetic and environmental factors are thought to trigger PD onset. Previously, we performed a genome-wide association study (GWAS) for PD and focused on candidate SNPs with the lowest P values. However, there seemed to be a number of polymorphisms which did not reach genome-wide significance threshold due to their low allele frequencies and odds ratios, even though they were truly involved in pathogenesis. Therefore we performed pathway analyses in order to overcome the limitations of conventional single-marker analysis and identify associated SNPs with modest effects. Each pathway analysis indicated that pathways related to immunity showed the strongest association with PD (DAVID, P=2.08×10(-6); i-GSEA4GWAS, P<10(-3); ICSNPathway, P<10(-3)). Based on the results of pathway analyses and the previously performed GWAS for PD, we focused on and investigated HLA-B and HLA-DRB1 as candidate susceptibility genes for PD. We typed HLA-B and HLA-DRB1 in 744 subjects with PD and 1418 control subjects. Patients with PD were significantly more likely to carry HLA-DRB1(∗)13:02 (P=2.50×10(-4), odds ratio=1.54). Our study provided initial evidence that HLA-DRB1(∗)13:02 and genes involved in immune-related pathways are associated with PD. Future studies are necessary to confirm these results and clarify the underlying mechanisms causing PD.

Gender-specific association between the COMT Val158Met polymorphism and openness to experience in panic disorder patients.

BACKGROUND: Because major depression and panic disorder are both more prevalent among females and since several lines of evidence suggest that genetic factors might influence an individual's vulnerability to panic disorder, gene-gender interactions are being examined in such psychiatric disorders and mental traits. A number of studies have suggested that specific genes, e.g. catechol-O-methyltransferase (COMT), might lead to distinct clinical characteristics of panic disorder. METHOD: We compared gender-specific personality-related psychological factors of 470 individuals with panic disorder and 458 healthy controls in terms of their COMT Val158Met polymorphism and their scores on the Revised NEO Personality Inventory (NEO PI-R) and State-Trait Anxiety Inventory (STAI) with a 1-way analysis of covariance. RESULTS: In the male panic disorder patients, the NEO PI-R score for openness to experience was significantly lower in the Met/Met carrier group, whereas there was no such association among the female panic disorder patients or the male or female control groups. CONCLUSION: The gender-specific effect of the COMT genotype suggests that the COMT Val/Met genotype may influence a personality trait, openness to experience, in males with panic disorder.

The Association of BDNF Val66Met Polymorphism With Trait Anxiety in Panic Disorder.

Recent studies indicate that early-onset panic disorder (PD) may show distinct clinical characteristics. The authors compared patients with early-onset PD, patients with late-onset PD, and healthy control subjects in terms of brain-derived neurotrophic factor (BDNF), the Val66Met polymorphism, State-Trait Anxiety Inventory (STAI) scores, and the Revised NEO Personality Inventory. In patients with early-onset PD, the STAI-T score was high in the Met/Met group, whereas the STAI-T score of the Val/Val group tended to be higher for healthy control subjects. The conflicting effect of the BDNF genotype between patients with early-onset PD and healthy control subjects suggests that the BDNF Met/Met genotype may increase trait anxiety in early-onset PD.

Irritable bowel syndrome, its cognition, anxiety sensitivity, and anticipatory anxiety in panic disorder patients.

AIM: The present study examined the effect of irritable bowel syndrome (IBS), cognitive appraisal of IBS, and anxiety sensitivity on anticipatory anxiety (AA) and agoraphobia (AG) in patients with panic disorder (PD). METHODS: We examined 244 PD patients who completed a set of questionnaires that included the Rome II Modular Questionnaire to assess the presence of IBS, the Anxiety Sensitivity Index (ASI), the Cognitive Appraisal Rating Scale (CARS; assessing the cognitive appraisal of abdominal symptoms in four dimensions: commitment, appraisal of effect, appraisal of threat, and controllability), and items about the severity of AA and AG. The Mini International Neuropsychiatric Interview was used to diagnose AG and PD. RESULTS: After excluding individuals with possible organic gastrointestinal diseases by using 'red flag items,' valid data were obtained from 174 participants, including 110 PD patients without IBS (PD/IBS[-]) and 64 with IBS (PD/IBS[+]). The PD/IBS[+] group had higher AA and higher comorbidity with AG than the PD/IBS[-] group. In the PD/IBS[+] group, the controllability score of CARS was significantly correlated with AA and ASI. Multiple regression analysis showed a significant effect of ASI but not of controllability on AA in PD/IBS[+] subjects. CONCLUSION: This study suggested that the presence of IBS may be related to agoraphobia and anticipatory anxiety in PD patients. Cognitive appraisal could be partly related to anticipatory anxiety in PD patients with IBS with anxiety sensitivity mediating this correlation.

Prepulse inhibition of auditory change-related cortical responses.

BACKGROUND: Prepulse inhibition (PPI) of the startle response is an important tool to investigate the biology of schizophrenia. PPI is usually observed by use of a startle reflex such as blinking following an intense sound. A similar phenomenon has not been reported for cortical responses. RESULTS: In 12 healthy subjects, change-related cortical activity in response to an abrupt increase of sound pressure by 5 dB above the background of 65 dB SPL (test stimulus) was measured using magnetoencephalography. The test stimulus evoked a clear cortical response peaking at around 130 ms (Change-N1m). In Experiment 1, effects of the intensity of a prepulse (0.5 ~ 5 dB) on the test response were examined using a paired stimulation paradigm. In Experiment 2, effects of the interval between the prepulse and test stimulus were examined using interstimulus intervals (ISIs) of 50 ~ 350 ms. When the test stimulus was preceded by the prepulse, the Change-N1m was more strongly inhibited by a stronger prepulse (Experiment 1) and a shorter ISI prepulse (Experiment 2). In addition, the amplitude of the test Change-N1m correlated positively with both the amplitude of the prepulse-evoked response and the degree of inhibition, suggesting that subjects who are more sensitive to the auditory change are more strongly inhibited by the prepulse. CONCLUSIONS: Since Change-N1m is easy to measure and control, it would be a valuable tool to investigate mechanisms of sensory gating or the biology of certain mental diseases such as schizophrenia.

Source localization of posterior slow waves of youth using dipole modeling.

AIM: Posterior slow waves of youth have a well-known electroencephalographic pattern that peaks in adolescence and usually disappears in adulthood. In general, posterior slow waves of youth are regarded as normal, but some reports have suggested that their presence is related to immature personalities or inappropriate social behavior. The physiological significance of this electroencephalographic pattern, however, remains unclear. The purpose of this study was to investigate the neural origins of posterior slow waves of youth using dipole source modeling. METHODS: Electroencephalographic epochs, including clear posterior slow waves of youth, were visually selected from electroencephalograms obtained from six normal adolescents using 25 scalp electrodes. The selected epochs were then averaged by arranging the negative peak of the slow waves at the occipital area of each epoch on the time axis. The averaged waveforms consisting of six right and one left posterior slow waves of youth were used for dipole source analysis. A single equivalent current dipole was estimated for the averaged waveforms. RESULTS: The best equivalent current dipoles were estimated to be located in or around the fusiform and middle occipital gyrus ipsilateral to the posterior slow waves of youth. CONCLUSIONS: The location of the estimated dipoles of posterior slow waves of youth was on the so-called ventral visual pathway. Further research is required to clarify the physiological significance of posterior slow waves of youth with respect to their origin.

Catechol-O-methyltransferase (COMT) Val158Met Polymorphism and Prepulse Inhibition of the Change-related Cerebral Response.

Change-related potentials elicited by an abrupt sound feature's change are attenuated by a leading weak sound (prepulse inhibition: PPI). We investigated whether the PPI index is associated with the catechol-methyltransferase (COMT) Val158Met polymorphism (rs4680), which is involved in the metabolism of dopamine in the prefrontal cortex. Healthy subjects with normal hearing were recruited (n = 70). A train of 100-Hz clicks 650 ms in duration was used. The test stimulus was an abrupt increase in sound intensity (+10 dB) from the baseline (70 dB) provided at 400 ms after the sound onset. Three consecutive clicks at 30, 40, and 50 ms before the change's onset were greater (+3 or +5 dB) from the baseline as a prepulse. The targeting auditory evoked potential component was Change-N1 peaking approx. 130 ms after the change onset. We calculated the inhibition level as the% inhibition of the Change-N1 amplitude by a prepulse. The %PPI in the Met-carriers was significantly greater than that in the Val/Val-individuals. Our results suggest that dopamine might play a role in the PPI of the change-related response. We propose that this index has the potential to identify an intermediate phenotype in psychiatric disorders such as schizophrenia.

An association analysis of Per2 with panic disorder in the Japanese population.

Panic disorder (PD) is a severe and chronic psychiatric disorder, with genetic components underlying in its etiology. The PERIOD2 (Per2) gene has been reported to be associated with familial advanced sleep phase syndrome. Considering the high frequency of sleep disturbance in PD, Per2 may be a candidate gene for PD. Therefore, we conducted a two-stage case-control association study in the Japanese population. In the first screening sample of 203 patients and 409 controls, we investigated three single-nucleotide polymorphisms in Per2. We found a potential association in the screening sample (rs2304672, genotype P=0.046, uncorrected), whereas we could not replicate the association in the second sample of 460 patients and 460 controls. Our results suggest that Per2 may not have a major role in the pathogenesis of PD in the Japanese population.

A genome-wide CNV association study on panic disorder in a Japanese population.

Family and twin studies have indicated that genetic factors have an important role in panic disorder (PD), whereas its pathogenesis has remained elusive. We conducted a genome-wide copy number variation (CNV) association study to elucidate the involvement of structural variants in the etiology of PD. The participants were 2055 genetically unrelated Japanese people (535 PD cases and 1520 controls). CNVs were detected using Genome-Wide Human SNP array 6.0, determined by Birdsuite and confirmed by PennCNV. They were classified as rare CNVs (found in <1% of the total sample) or common CNVs (found in ≥5%). PLINK was used to perform global burden analysis for rare CNVs and association analysis for common CNVs. The sample yielded 2039 rare CNVs and 79 common CNVs. Significant increases in the rare CNV burden in PD cases were not found. Common duplications in 16p11.2 showed Bonferroni-corrected P-values <0.05. Individuals with PD did not exhibit an increased genome-wide rare CNV burden. Common duplications were associated with PD and found in the pericentromeric region of 16p11.2, which had been reported to be rich in low copy repeats and to harbor developmental disorders, neuropsychiatric disorders and dysmorphic features.

Association of RGS2 variants with panic disorder in a Japanese population.

Panic disorder (PD) is a severe and chronic psychiatric disorder with significant genetic components underlying its etiology. The gene regulator of G protein signaling 2 (RGS2) has been reported to be associated with anxiety disorders. To confirm the association of RGS2 with PD, we investigated three single nucleotide polymorphisms (SNPs) of RGS2 (rs10801152, rs4606, and rs1819741) in 677 Japanese PD cases and 460 controls. The SNP rs10801152 was suggestive of an association with PD (allele P = 0.045 adjusted using sex and age as confounding factors). The three-SNP haplotype was significantly associated with PD (global permutation P = 4 × 10(-4)). The haplotypes T-G-C and T-C-T showed significant association and protective effect on PD (T-G-C, permutation P = 0.038, OR = 0.80, 95%CI = 0.68-0.95; T-C-T, permutation P = 0.004, OR = 0.38, 95%CI = 0.21-0.70). These results provide support for an association of RGS2 with PD in a Japanese population.

Shared transethnic genetic basis of panic disorder and psychiatric and related intermediate phenotypes.

Panic disorder (PD), a common anxiety disorder, is modestly heritable. The genetic basis of anxiety disorders overlaps with that of other psychiatric disorders and their intermediate phenotypes in individuals of European ancestry. Here, we investigated the transethnic polygenetic features shared between Japanese PD patients and European patients with psychiatric disorders and their intermediate phenotypes by conducting polygenic risk score (PRS) analyses. Large-scale European genome-wide association study (GWAS) datasets (n = 7,556-1,131,881) for ten psychiatric disorders and seven intermediate phenotypes were utilized as discovery samples. PRSs derived from these GWASs were calculated for Japanese target subjects [718 PD patients and 1,717 healthy controls (HCs)]. The effects of these PRSs from European GWASs on the risk of PD in Japanese patients were investigated. The PRSs from European studies of anxiety disorders were marginally higher in Japanese PD patients than in HCs (p = 0.013). Regarding other psychiatric disorders, the PRSs for depression in European patients were significantly higher in Japanese PD patients than in HCs (p = 2.31×10-4), while the PRSs for attention-deficit/hyperactivity disorder in European patients were nominally lower in Japanese PD patients than in HCs (p = 0.024). Regarding health-related, personality-based and cognitive intermediate phenotypes, the PRSs for loneliness (especially isolation) in European individuals were significantly higher in Japanese PD patients than in HCs (p = 9.02×10-4). Furthermore, Japanese PD patients scored nominally higher than HCs in PRSs for neuroticism in European people (p = 3.37×10-3), while Japanese PD patients scored nominally lower than HCs in PRSs for tiredness (p = 0.025), educational attainment (p = 0.035) and cognitive function (p = 9.63×10-3). Our findings suggest that PD shares transethnic genetic etiologies with other psychiatric disorders and related intermediate phenotypes.

Internet-Based Individualized Cognitive Behavioral Therapy for Shift Work Sleep Disorder Empowered by Well-Being Prediction: Protocol for a Pilot Study.

BACKGROUND: Shift work sleep disorders (SWSDs) are associated with the high turnover rates of nurses, and are considered a major medical safety issue. However, initial management can be hampered by insufficient awareness. In recent years, it has become possible to visualize, collect, and analyze the work-life balance of health care workers with irregular sleeping and working habits using wearable sensors that can continuously monitor biometric data under real-life settings. In addition, internet-based cognitive behavioral therapy for psychiatric disorders has been shown to be effective. Application of wearable sensors and machine learning may potentially enhance the beneficial effects of internet-based cognitive behavioral therapy. OBJECTIVE: In this study, we aim to develop and evaluate the effect of a new internet-based cognitive behavioral therapy for SWSD (iCBTS). This system includes current methods such as medical sleep advice, as well as machine learning well-being prediction to improve the sleep durations of shift workers and prevent declines in their well-being. METHODS: This study consists of two phases: (1) preliminary data collection and machine learning for well-being prediction; (2) intervention and evaluation of iCBTS for SWSD. Shift workers in the intensive care unit at Mie University Hospital will wear a wearable sensor that collects biometric data and answer daily questionnaires regarding their well-being. They will subsequently be provided with an iCBTS app for 4 weeks. Sleep and well-being measurements between baseline and the intervention period will be compared. RESULTS: Recruitment for phase 1 ended in October 2019. Recruitment for phase 2 has started in October 2020. Preliminary results are expected to be available by summer 2021. CONCLUSIONS: iCBTS empowered with well-being prediction is expected to improve the sleep durations of shift workers, thereby enhancing their overall well-being. Findings of this study will reveal the potential of this system for improving sleep disorders among shift workers. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000036122 (phase 1), UMIN000040547 (phase 2); https://tinyurl.com/dkfmmmje, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046284. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24799.